Despite recent progress in understanding molecular aspects of endotoxemia and development of novel therapies, mortality remains high in horses with severe abdominal crises, such as intestinal ischemia, salmonellosis, and neonatal septicemia (Morris 1991; Welch et al. 1992). In these acute inflammatory diseases, the immune response is triggered with cytokines and inflammatory mediators being released, and platelets being activated either by endotoxin, released from gram negative bacteria, and/or the coagulation cascade (Weiss and Rashid 1998). Those events result in vascular injury and possibly thrombosis, which is the final and often fatal outcome of these disorders.
The initial step in the inflammatory reaction begins with the tethering and rolling of the circulating leukocytes on an activated endothelium (McEver and Cummings 1997). The rolling process is mediated by a family of Ca2+-dependent proteins, the selectins. Those membrane-bound selectins are expressed within the vasculature, on the surface of endothelial cells (P- and E-selectin), leukocytes (L-selectin), and platelets (P-selectin). As members of the selectin family, they all contain a C-type carbohydrate recognition domain at their N-terminus which plays a crucial role in interacting with their ligand proteins. Human P-selectin mediates leukocyte adhesion via its natural ligand, P-selectin glycoprotein ligand-1 (hPSGL-1), which is located on the surface of a variety of leukocytes, including neutrophils, monocytes, eosinophils, and lymphocytes (Hicks et al. 2002). In humans, the interaction between platelet P-selectin and leukocyte PSGL-1 plays a central role in inflammatory and thrombotic mechanisms in ischemic conditions by regulating leukocyte trafficking through cell adhesion, platelet-leukocyte aggregate formation and tissue factor expression (Cummings 1999; Moore 1998). Those human disorders share comparable pathomorphological features with intestinal ischemia, colitis, and neonatal septicemia in the equine. Recently, the inventor discovered that a high proportion of circulating equine platelets are in a primed state with high baseline level of P-selectin expression and require minimal stimulation to form aggregates (Lalko et al. 2003). As a result of the high basal state of platelet P-selectin expression, it is reasonable to propose that horses are predisposed to inflammatory and thrombotic disorders during gram-negative septicemia and endotoxemia as a result of enhanced platelet-leukocyte interaction via equine PSGL-1 (ePSGL-1).
It can be appreciated that there exists a need in veterinary medicine for improved methods of treating equine subjects susceptible to or suffering from acute inflammatory responses and thrombotic disorders. Methods to universally combat inflammatory and thrombotic disorders are highly sought after and their discovery would be welcomed by equine owners and veterinarians alike.